Naove T cells are essential components of vertebrate immune systems. In healthy individuals, naove CD4 (T helper) and CD8 (cytotoxic T cell) numbers are maintained at remarkably constant levels, despite declining input of new cells from the thymus and loss through differentiation into effectors or memory cells following exposure to pathogens. Signals through the T cell receptor derived from contact with self-antigens and cytokines, most notably IL-7, are known to play important roles in the homeostatic regulation of naove T cells. These signals are likely obtained competitively as naove T cells transit through lymph nodes. However, we lack an overarching view of how thymic input and the regulation of peripheral naove T cells by TCR and IL-7 signals combine to dictate naove T cell population dynamics, and precisely how the control of cell numbers is achieved. Identifying these mechanisms is the long-term objective of our study. A more complete understanding of naove T cell homeostasis will aid the design of more effective treatments to restore T cell populations following insults such as lymphopenia induced by radiation therapy or HIV infection. The Specific Aims are the following. (1) To identify the topologies of the signal processing that integrates IL-7 receptor and TCR signals in CD4 and CD8 cells. (2) To establish whether these signals also play a role in the maturation of recent thymic emigrants, and whether competition between T cells for these signals limits the incorporation of RTE into the mature pool. This is important for understanding the impact of therapies to increase thymic output. (3) To analyze the relationship between the rate of transit of T cells through lymph nodes and their survival, and how contacts with cells providing homeostatic stimuli influence these rates of transit. PUBLIC HEALTH RELEVANCE: Naove T lymphocytes are circulating white blood cells that are renewed and maintained at remarkably constant numbers throughout an individual's lifetime and are essential for immunity to infections. In this project we aim to understand how naove T lymphocytes sense and process information from their environment to regulate their numbers. This understanding will help us develop better treatments for restoring T lymphocytes that are lost following, for example, radiation therapy or HIV infection.